Oxidation-chlorination of 3-hydroxysteroids



Unitcd States Patent OXIDATION-CHLORINATION OF 3-HYDROXYSTEROIDS GuntherS. Fonken, Kalamazoo, Robert H. Levin, Kalamazoo Township, KalamazooCounty, and A Vern McIntosh, J12, Kalamazoo, Mich., assignors to TheUpjohn Company, Kalamazoo, Mich., a corporation of Michigan No Drawing.Application July 16, 1952, Serial No. 299,233

Claims. (Cl. 260397.45)

This invention relates to steroid compounds, and is more particularlyconcerned with a novel, industrially important process for theconversion of 3-hydroxysteroids to 4-chloro-3-ketosteroids in highyields by the action of an organic hypochlorite, preferably an alkylhypochlorite, and with the novel steroids thus-produced.

It is an object of the present invention to provide a novel commerciallysignificant process for the concomitant chlorination and oxidation ofB-hydroxysteroids to 4-chloro-3-ketosteroids in high yields. Anotherobject is the provision of certain novel and useful 4-chloro-3-ketosteroids. Other objects of this invention will be apparent to thoseskilled in the art to which this invention pertains.

4-chloro-3-ketosteroids are valuable precursors to physiologicallyactive steroids. 3a,17a-dihydroxy-21- acetoxypregnane-l1,20-dione, forexample, can be concomitantly chlorinated and oxidized to the novel 4-chloro 17a hydroxy-Zl-acetoxypregnane-3,l1,20-trione, which canthereafter be dehydrohalogenated by procedure well-known in the art, toproduce cortisone acetate. Moreover, 4-chloro-3-ketosteroids have beenfound to be very stable compounds and can be kept for long periods oftime without noticeable decomposition. Since most physiologically activehormone and hormonelike steroids possess a A -3-keto group, a processwhich produces a 3-keto group and a 4-chloro group, concomitantly andwithout extensive manipulation or the necessity of carefully controlledconditions, is of considerable industrial importance. A furtheradvantage of the process of the present invention resides in the factthat the chlorination is achieved without the use of chlorine gas, theprior art use of which was sufficiently inconvenient and unsatisfactoryto reduce interest in the chlorination of steroids to a minimum.Moreover, the process of the present invention is conveniently performedat about room temperature, e. g., between about twenty and about thirtydegrees centigrade, usually Without external heating or cooling, thusadding to the con venience, simplicity, and economy of the process.

The process of the present invention, besides being a simple,economical, and convenient method of converting a 3-hydroxysteroid to a4-chloro-3-ketosteroid in one step, is especially advantageous in thatyields of desired product are frequently obtained in excess of ninetypercent of the theoretical, as illustrated by Example 1. The productthus-obtained is sufficiently pure for most purposes and does notusually require purification. These results are economically veryimportant since the prior art two-step methods of oxidation andchlorination of 3-hydroxy steroids involve isolations and purifications,usually in both steps, with resulting reduction in yields. Other usesand advantages of this industrially significant invention will beapparent to those skilled in the art to which this invention pertains.

Preferred starting compounds of the present invention are3-hydroxysteroids having the normal configuration at the S-carbon atom,Which are unsubstituted at 2,714,600 Patented Aug. 2, 1955 the4-position, which are saturated (i. e., carbon to carbon double andtriple-bonds are not present), and which do no thave unsubstitutedprimary or secondary hydroXyl groups other than the 3-hydroxyl group,since these unsaturated linkages and hydroxyl groups, which also usuallyreact with organic hypochlorites, sometimes unduly complicate thereaction. Steroids of the above type, but containing, in addition, an11oc(01 B)-hydroxyl group, are also included as preferred startingcompounds since the llot-hydroxyl group usually is unaffected by alkylhypochlorites, and the llfl-hydroxyl group is smoothly converted to anll-ketonic oxygen by using two additional molar equivalents of the alkylhypochlorite. This delineation of preferred starting compounds, however,is not to be construed as limiting the scope of this invention. Other3-hydroxy steroids which are converted to 4-chloro-3-ketosteroids by theprocess of this invention are also included as starting materials Withinthe scope of this invention. If additional groups such as, for example,unsaturated linkages or other hydroxyl groups, or other groupings, arepresent which are reactive with the alkyl hypochlorite under theconditions of the reaction, an additional amount of the organichypochlorite may be included in the reaction mixture to react with theseadditional groups. Alternatively these additional reactive groups in thestarting compounds may be protected and later regenerated in the productobtained by the process of the present invention, for example, carbon tocarbon double-bonds may be protected by adding two bromine atoms andlater regenerated by treating with zinc. Additional hydroxyl groups maybe protected, for example, by selective ester or ether formation andlater regenerated by hydrolysis. In some instances chlorination occursat a position other than the 4-position, e. g., at the 2-position when a3-hydroxyallosteroid is employed as starting material.

Preferred starting normal 3a(or fi)-hydroxysteroids of particularinterest are those having the following structural formula:

wherein R is a-hydroxy or B-hydroxy; R1 is hydrogen, a-hydroxy or anacyloxy ester thereof, such as, for example, formyloxy, acetoxy,benzoyloxy, propionoxy, butyryloxy, valeryloxy, hexanoyloxy,phenylacetoxy, octanoyloxy, or the like, especially lower-alkanoyloxy,or ,B-hydroxy, or ketonic oxygen; R2 is hydrogen or hydroxy; and R3 isacetyl, acyloxyacetyl, e. g., acetoxyacetyl, propionoxyacetyl,butyryloxyacetyl, octanoyloxyacetyl, benzoyloxyacetyl, or the like,especially acyloxyacetyl wherein the acyloxy group is alower-alkanoyloxy group, or haloacetyl, e. g., bromoacetyl,chloroacetyl, or the like.

According to the method of the present invention, a S-hydroxysteroid iscontacted, in the presence of water, with an organic hypochlorite, andpreferably with an alkyl hypochlorite.

In carrying out the process of the present invention, a 3-hydroxysteroidis contacted, in the presence of from a trace to about twenty percent ofwater based upon the total weight of the reaction mixture, with anorganic hypochlorite, preferably an alkyl hypochlorite. The reaction isusually conducted in the presence of an organic solvent such as, forexample, tertiary-butyl alcohol, tertiary-amyl alcohol, chloroform,ethylene dichloride, or the like, the concept, definition, and use of asolvent being well-known in the art. The employed temperature is usuallybetween about minus ten and about plus fifty degrees centigrade,ordinarily at about room temperature, e. g., between about twenty andabout thirty degreescentigrade, for a reaction period of between aboutten minutes and about twenty-four hours, the exact time required forcomplete reaction being in part dependent upon the reaction temperatureand the particular hypochlorite and solvent employed, as well as otherfactors apparent to one skilled in the art.

Although the use of organic hypochlorites generally is within thepurview of the present invention, alkyl hypochlorites are usually used.The secondary-alkyl hypochlorites, however, are relatively unstable andfor this reason are not the preferred hypochlorites. Since methylhypochlorite is extremely unstable and even explosive in certaininstances, it is preferably not employed in carrying out the process ofthe present invention. The tertiary-alkyl hypochlorites have been foundto be particularly satisfactory organic hypochlorites, being quitestable, and of these, tertiary-butyl hypochlorite has been used withrepeated success and is therefore a preferred alkyl hypochlorite. Bestyields of the desired 4-chloro- 3-ketosteroids appear to be obtainedwhen the alkyl hypochlorite is employed in the molar ratio to starting3-hydroxysteroid of at least about two to one, preferably from about 2.2to about 2.5 moles of alkyl hypochlorite to one mole of startingsteroid. Large molar excesses of alkyl hypochlorite do not appear to beadvantageous and may even be disadvantageous in certain instances.However, if an additional group which reacts with the alkyl hypochloriteis present, the amount of alkyl hypochlorite is increased by the amountrequired to react with the additional group.

While considerably broader ranges of reaction temperature, e. g.,between about minus ten and about plus fifty degrees centigrade, areincluded within the scope of the present invention, the preferredreaction temperature is at or about room temperature, e. g., betweenabout twenty and about thirty degrees centigrade, as high yields ofdesired product are obtained at this temperature and external cooling orheating is usually unnecessary. Sometimes, however, a reactiontemperature slightly below room temperature will enhance the yield ofdesired product when the reaction is unduly accompanied by undesirableside reactions. Usually reaction temperatures substantially above roomtemperature are not preferred. In general the preferred reacchloroform,ethylene dichloride, pentane, hexane, and .2;

the like, are also suitable. The choice of reaction solvent depends inpart on the solubility of the starting steroid in the solvent.

The presence of water is an important factor in carrying out the processof the present invention. Water is, therefore, always present in thereaction mixture, from 0.5 percent to about twenty percent of the totalreaction mixture by weight being the usual operating limits.

When only a trace of water is present, the yields of desired product areless than optimum, and when more than twenty percent water, based on thetotal reaction weight is employed, the reaction is usually sluggish andrequires long periods of time for completion of the reaction. Usuallyabout two to about six percent water gives the best yields of product.

It has also been found that the addition of a strong acid such as, forexample, hydrochloric, sulfuric, benzenesulfonic, para-toluenesulfonicacid, or the like, and particularly hydrochloric acid, to the reactionmixture enhances the yield of desired product and preferred operatingconditions include the addition of from about 0.5 mole to about 1.5moles of hydrochloric acid per mole of steroid to the reaction mixture.The reaction can be carried out in the presence or absence of light.

Isolation of the desired product of the reaction is convenientlyachieved by distilling the volatile components of the reaction mixtureat reduced pressure, leaving the steroid product as the distillationresidue. Quite frequently, especially when using tertiary-butyl alcoholas reaction solvent, the desired reaction product crystallizes from thereaction mixture in a state of high purity and does not require furtherpurification. Purification of the reaction product can be achieved,however, if desired, by crystallization from a solvent such as, forexample, methanol, ethanol, ether, chloroform, methylene dichloride, orthe like, or by adsorption and elution on a chromatographic columnaccording to methods wellknown in the art.

The progress of the oxidation can conveniently be followed by iodometrictitration, according to methods known in the art, of aliquot samplestaken from time to time from the reaction mixture. When consumption ofalkyl hypochlorite has essentially ceased or when the theoretical amounthas been consumed, the reaction is usually complete and further reactiontime is unnecessary.

An especially preferred method of carrying out the process of thepresent invention involves dissolving the selected 3-hydroxysteroid in asolvent, preferably tertiary-butyl alcohol, and contacting the solutionwith from about 2.2 to about 2.5 molar equivalents of an alkylhypochlorite, preferably tertiary-butyl hypochlorite, in the presence offrom about 0.5 to about 1.5 molar equivalents of dilute hydrochloricacid for from about ten minutes to about twenty-four hours. When thereaction is complete, the solvent may be distilled at about roomtemperature at reduced pressure and the steroid product obtained as thedistillation residue.

The following examples are illustrative of the process and products ofthe present invention but are not to be construed as limiting.

PREPARATION l.3 a, l 7ct-DIHYDROXYPREGNANE-l 1,20-

DIONE ZO-ETI-IYLENE GLYCOL KETAL A mixture of 260 milligrams of3a,l7a-dihydroxypregnane-ll, ZO-dione fKritchevsky, Garmaise, andGallagher, J. Am. Chem. Soc., 74, 483 (1952)], five milliliters ofethylene glycol, fifty milligrams of para-toluenesulfonic acidrnonohydrate and 100 milliliters of benzene was placed in a reactionflask which was equipped with a reflux condenser and a water trap soarranged that the condensed vapors passed through the water trap beforereturning to the reaction flask. The mixture was heated to reflux andwas allowed to reflux for five hours while at the same time beingagitated. The water which formed was removed by co-distillation withbenzene and was collected in the water trap. The reaction mixture wascooled and poured into a dilute solution of sodium bicarbonate. Thebenzene layer was separated, washed with water, dried and concentratedto dryness. The residue was chromatographed over forty grams of Florisilmagnesium silicate using eighty-milliliter portions of a mixture ofethylene dichloride with successively greater proportions of acetone forelution. The material, which was eluted with ethylene dichloride-acetone(12:1 and 8:1), weighed 141 milligrams after removal of the solvents.Recrystallization from benzene-Skelly Solve B gave fifty milligrams of3u,l7a-dihydroxypregnane-11,20- dione 20-ethylene glycol ketal meltingat 144 to 146 degrees centigrade.

PREPARATION 2.3 a, 1 1 a,17a-'IRIHYDROxYPREGNAN-20- oNE AND 3 05,11,6,17a-TRmYnRoxYPREoNAN--oNE To a solution of two grams of lithiumaluminum hydride in 200 milliliters of anhydrous ether was addeddropwise, with stirring, two grams of3a,17a-dihydroxypregnane-11,20-dione 20-ethylene glycol ketal fromPreparation 1 in twenty milliliters of anhydrous benzene. The mixturewas then stirred at room temperature for one hour followed by boilingunder reflux for an additional hour. With continued stirring theresulting mixture was cooled and treated cautiously with water addeddropwise. The resulting solution containing the:,1l,l7a-trihydroxypregnan-20-one 20-ethylene glycol ketals then wasadmixed with a ten-fold excess of dilute hydrochloric acid and theresulting heterogeneous mixture was stirred vigorously for twenty hoursat room temperature. The product was isolated by separating the organicand aqueous layers, extracting the aqueous layer with ether, combiningthe ether extract with the organic layer, washing the organic solutiontwice with water, drying the washed solution over anhydrous sodiumsulfate, removing the drying agent by filtration, removing the solventsby distillation under reduced pressure, dissolving the resultingresidual oil in ethyl acetate, and adding Skelly Solve B to give anopalescent solution.

The crystals obtained (Crop A), 540 milligrams, were .9

removed by filtration, and an additional quantity of Skelly Solve B wasadded to the filtrate. The crystals obtained from the diluted filtrate(Crop B) were separated by filtration weighing 590 milligrams. Anadditional quantity of crystals identical with those of Crop B wasobtained from the remaining mother liquor by distillation of thesolvents under reduced pressure, redissolving the residual oil in aminimum amount of ethyl acetate, and diluting with Skelly Solve B.

Crop A was recrystallized twice from a mixture of ethyl acetate andSkelly Solve B and once from a mixture of acetone and Skelly Solve B togive 240 milligrams of 312,11a,17a-trihydroxypregnan-ZO-one as needles;melting point 184-186 degrees centigrade; [M plus 52 degrees in acetone.

Analysis:

Calculated for C21Hs404 C, 71.9; H, 9.71 Found C, 72.2; H, 9.53

Crop B was recrystallized once from a mixture of ethyl acetate andSkelly Solve B and once from a mixture of acetone and Skelly Solve B togive 275 milligrams of 3a,11/8,17ot-trihydroxypregnan-20-one as plates;melting point 213-216 degrees centigrade; [11.1 plus 73 degrees inacetone.

Analysis:

Calculated for C21H34Oi C, 71.9; H, 9.71 Found C, 72.1; H, 9.81

PREPARATION 3 .3 fl-ACETOXYPREGNANE-l 1,20-DI0NE3fl-hydroxypregnane-11,20-dione [Von Euw, Lardon, and Reichstein, Helv.Chim. Acta, 27, 821 (1944)], 8.18 grams, was dissolved in a mixture offifty milliliters of acetic anhydride and two milliliters of pyridine,and the resulting solution was allowed to stand at room temperature for24 hours. The mixture was then poured into 325 milliliters of water andallowed to stand at room temperature for several hours to permitdecomposition of the excess acetic anhydride. The solid product wasremoved byfiltration and dried under vacuum. Two recrystallizations fromaqueous acetone gave 2.75 grams, melting point 155-162 degreescentigrade. Repeated recrystallization from aqueous acetone gave3,6-acetoxy- 6 pregnane-11,20-dione; melting point 164-165 degreescentigrade; [M plus 99 degrees in chloroform.

Analysis:

Calculated for C23Ha404 C, 73.90; H, 9.10 Found C, 73.69; H, 9.02

PREPARATION 4-35, 1 1,20'TRIACETOXY-9U 1), 17(20)- PREGNADIENE A mixtureof 2.75 grams of 3p-acetoxypregnane-11,20- dione from Preparation 3,0.73 gram of para-toluenesulfonic acid mono-hydrate, and ninetymilliliters of acetic anhydride was heated to boiling and allowed todistil slowly for three hours, '71 milliliters of distillate beingcollected. Another fifteen milliliters of distillate was collected bydistillation under reduced pressure, and the resulting residue wascooled, diluted with milliliters of ether, washed with one percentaqueous sodium bicarbonate solution and with water, and dried overanhydrous sodium sulfate. After removing the drying agent by filtration,the ether was removed by distillation giving 3.5 grams of35,11,20-t1iacetoxy 9(11),l7(20) pregnadiene as a glass.

PREPARATION 5.17(20)-oxIno-3 18,1 1,20-rRIAcEToxY- 9(1 l)-PREGNENE3,6,11,20 triacetoxy 9(l1),17(20) pregnadiene, 3.5 grams, fromPreparation 4 was dissolved in seventeen milliliters of chloroform andthe resulting solution cooled to a temperature of zero to five degreescentigrade. A mixture of 170 milligrams of anhydrous sodium acetate and7.7 milliliters of 38 percent peracetic acid was added with stirring,the temperature of the reaction mixture being maintained at zero to fivedegrees centigrade. The resulting mixture was stirred at thistemperature for ten minutes, then allowed to come to room temperature,and stirred for an additional ninety minutes. The mixture then wasdiluted With eighty milliliters of ether, washed with fourfifteen-milliliter portions of five percent aqueous sodium hydroxidesolution, and three fifteenmilliliter portions of water, and dried overanhydrous sodium sulfate. Removal of the drying agent by filtration anddistillation of the solvents under reduced pressure gave 3.5 grams of17(20)-oxido-3;8,11,20-triacetoxy- 9(11)-pregnene as a viscous oil.

PREPARATION 6.3 B, 1 7 ot-DIHYDROXYPREGNANE- 1 1,20- DIONE The17(20)-oxido-3,8,11,20-triacetoxy-9(1 1 )-pregnene from Preparation 5,3.5 grams, was dissolved in 66 milliliters of alcohol, 66 milliliters of0.5 normal aqueous sodium hydroxide solution added, and the resultingmixture stirred for thirty hours at room temperature under a nitrogenatmosphere. The mixture was poured into 250 milliliters of water, andthe resultant slurry extracted with four fifty-milliliter portions ofchloroform. Distillation of the extraction solvent gave 2.74 grams ofcrude 3p,17ot-dihydroxypregnane-11,20-dione.

PREPARATION 7 .-3 p, 17 u-DIHYDROXYPREGNANE-l 1,20- DIONE ZO-ETHYLENEGLYcoL KETAL In the same manner as given in Preparation 1, 3 3,171:-dihydroxypregnane-l1,20-dione ZO-ethylene glycol ketal is prepared from3,8,17a-dihydroxypregnane-11,20-dione from Preparation 6 by reactionwith ethylene glycol in the presence of para-toluene-sulfonic acid.

PREPARATION 8.-3p,1 1oz,17ot-TRIHYDROXYPREGNAN-20- oNE AND35,1lfl,17a-TRIHYDROXYPREGNAN-20-ONE One gram of3p,l7a-dihydroxypregnane-11,20-dione 20-ethylene glycol ketal fromPreparation 7 was dissolved in fifteen milliliters of benzene, reducedwith one gram of lithium aluminum hydride in milliliters of ether, andsubsequently hydrolyzed with acid using the procedure of Preparation 2.The ratio was about three 7 parts of3,8,11a,17a-trihydroxypregnan-ZO-one to about five parts of35,11t9,17u-trihydroxypregnan-ZO-one.

Analysis of 3/111a,17a-trihydroxypregnan-ZO-ohe:

PREPARATION 9.1 lot-HYDROXYPROGESTERONE A medium was prepared from fivemilliliters of corn steep liquor, twenty grams of Edamine commerciallactalbumin digest, and fifty milligrams of Cerelose commercialdextrose, per liter of tap water and adjusted to a pH of between about5.5 and about 5.9. To four liters of this medium containing a 32 to 48hour growth, at room temperature with aeration, of Rhizopus arrhizus,was added one gram of progesterone in fifty milliliters of acetone. Theculture was then incubated at room temperature for 48 hours. At the endof this time the pH of the medium was 3.5 and the fermentation liquorand mycelia were extracted successively with three one-liter portions,one two-liter portion, and one one-liter portion of methylene chloride.The methylene chloride extracts were combined and washed with two100-milliliter portions of two percent aqueous sodium bicarbonatesolution and three SOD-milliliter portions of water. The methylenechloride extract was evaporated to dryness in vacuo and the solids takenvup in fifty milliliters of methylene chloride. The solution wastransferred to a l-milliter beaker and evaporated by a stream of air.The solids, weighing 1.585 grams, were dissolved in five milliliters ofhot methanol and allowed to cool slowly at room temperature, whereupon75 milligrams of crystals separated out. The mother liquor was freed ofsolvent by aeration, dissolved in fifty milliliters of benzene, andchromatographed over alumina (A1203). Fifty grams of acid-washedalumina, dried at 45 degrees centigrade, was used as adsorbent and100-milliliter portions of solvents were used to develop the column. Thesolvents and the order used were as follows: benzene, benzene, benzeneplus 5 percent ether, benzene plus 5 percent ether, benzene plus percentether, benzene plus 10 percent ether, benzene plus 10 percent ether,benzene plus 50 percent ether, benzene plus 50 percent ether, ether,ether, ether plus 5 percent chloroform, ether plus 5 percent chloroform,ether plus 10 percent chloroform, ether plus 10 percent chloroform,ether plus 50 percent chloroform, ether plus 50 percent chloroform,chloroform, chloroform, chloroform plus 5 percent acetone, chloroformplus 5 percent acetone, chloroform plus 10 percent acetone, chloroformplus 10 percent acetone, chloroform plus 50 percent acetone, chloroformplus 50 percent acetone, acetone, acetone, acetone plus 5 percentmethanol, acetone plus 5 percent methanol, acetone plus 10 percentmethanol, acetone plus 10 percent methanol, acetone plus 50 percentmethanol, acetone plus 50 percent methanol. The chloroform andchloroform plus five percent acetone eluates were combined, evaporatedto dryness, and the residue dissolved in two milliliters of hot methanoland filtered. After overnight refrigeration, 171 milligrams ofcrystalline llot-hydroxyprogesterone, melting at 166 to 167 degreescentigrade, was obtained. A sample recrystallized from methanol gave thefollowing constants: melting point, 166-167 degrees centigrade [111 plus175.9 degrees (chloroform).

Analysis:

Calculated for C21H30Os C, 76.4; H, 9.10 Found C, 76.6; H, 8.92

The structure of this product was further established by its conversion,with chromic acid in acetic acid, to 11-ketoprogesterone [Reichstein,Helv. Chim. Acta, 23, 684 (1940); ibid., 26, 721 (1943)].

PREPARATION 10.11a-HYDROXYPREGNANE-3,ZO-DIONE A solution of 250milligrams of lla-hydroxyprogesterone from Preparation 9 in 100milliliters of ethanol containing six drops of triethylamine wassubjected to hydrogenation at room temperature under a pressure of aboutten pounds of hydrogen in the presence of milligrams of a thirty percentpalladium-charcoal catalyst in a Parr apparatus with an auxiliarymercury manometer. The time required for the hydrogenation was abouttwenty minutes. The reaction mixture was filtered and the solvent wasevaporated to yield 265 milligrams of material melting at 145185 degreescentigrade. This product was extracted with a mixture of one milliliterof ether and nine milliliters of Skelly Solve B. On standing, theextract deposited eighty milligrams (32 percent) of lla-hydroxypregnane3,20 dione as feathery needles which melted at -90 degrees centigrade.Recrystallization from a mixture of about six drops of ethyl acetate andfive milliliters of Skelly Solve B did not change the melting point.

Analysis:

Calculated for C21H32O3 C, 75.86; H, 9.70 Found C, 76.13; H, 9.63

PREPARATION 1 1.3 a, 1 1 ot-DIHYDROXYPREGNAN-ZO-ONE To a solution of5.31 grams of llot-hydroxypregnane- 3,20-dione of Preparation 10 inmilliliters of peroxide-free dioxane maintained at fifty degreescentigrade in a water bath was added a solution of 195.5 milligrams ofsodium borohydride (assay 84 percent) in five milliliters of water. Themixture was stirred for one hour at fifty degrees centigrade, filtered,acidified with three normal aqueous hydrochloric acid solution, andevaporated under reduced pressure. The residue was crystallized fromfifty milliliters of ethyl acetate to give 1.95 grams (36 percent) of3a,11o-dihydroxypregnan- 20-one, which melted at 180-182 degreescentigrade. An additional 0.2 gram melting at 181183 degrees centigradewas obtained from the filtrate, total yield, 2.15 grams (40 percent).

PREPARATION 12.1 lot-ACETOXYPREGNANE-3 ,ZO-DIONE A mixture of 70.5milligrams of lla-hydroxypregnane- 3,20-dione from Preparation 10, 0.8milliliter of acetic anhydride and 0.7 milliliter of pyridine wasallowed to stand for sixteen hours at room temperature and then pouredinto ice water. The precipitated product was isolated by filtration anddried. The yield of llu-acetoxypregnane'-3,20'- dione, melting at1435-1465 degrees centigrade, was 67 milligrams (84 percent). After onerecrystallization from ether-Skelly Solve B, the melting point was -151degrees centigrade; [a] --plus 63 degrees (c=0.803 in chloroform).

Analysis:

Calculated for C23H34O4 C, 73.76; H, 9.15 Found C, 73.93; H, 9.32

In the same manner, other 11a-acyloxypregnane-3,20 diones are preparedfrom 11a -hydroxypregnane 3,20- dione, including 110: formyloxypregnane3,20 dione (using formic acid as the acylating agent);lla-propionoxypregnane-3,20-dione; llu-butyryloxypregnane 3,20- dione;11a-octanoyloxypregnane-3,ZO-dione; and the like.

PREPARATION 13 .3 a, 1 10,ZO-TRIACETOXY-l7 (20) PREGNENE Four hundredand five (405) milligrams of 30:,11a-dihydroxypregnan-ZO-one fromPreparation 11, 200 milligrams of paratoluenesulfonic acid monohydrateand seventy milliliters of acetic anhydride were heated to distillationtemperature and allowed to distil slowly for three and one-half hours. Atotal of sixty milliliters of distillate was collected. The residue wascooled to room temperature, poured into ice-water, and the resultingcrystalline product collected and Washed with water.

PREPARATION 14.-3;9,1 1a,20-TRIACETOXY-17(20)- PREGNENE Using theprocedure described in Preparation 13, 35- hydroxy-11a acetoxypregnan20-one (prepared by the reduction of the 11a-acetoxypregnane-3,20-dioneof Preparation 12 with hydrogen at two to three atmospheres pressure inmethanol at room temperature using a Raney nickel catalyst), isconverted to 3B,11a,20-triacetoxyl7(20)-pregnene with acetic anhydridein the presence of para-toluenesulfonic acid.

In the same manner as given above in Preparation 13 and Preparation 14,other 304(01 p),11a,20-triacyloxy- 17 (20)-pregnenes are prepared,including 3a,11ot,20-tllpropionoxy-17 (20)apregnene; 3,6,11a,20tri'propionoxy- 17(20) -pregnene; 36,20 diacetoxy-lla formyloxy- 17(20)pregnene; 35,20 dipropionoxy-lla acetoxy- 17(20)-pregnene; 30L,11a,20trioctanoyloxy 17(20)- pregnene; 3 B,20-dioctanoyloxy-1 1apropionoxy-17(20)- pregnene; 3 a, 1 la,20-tributyroyloxy- 17 (20)-pregnene; 3 a, 1lot,20-trivaleroyloxy 17(20)-pregnene; 3a,1la,20-trihexanoyloxy 17(20) pregnene; 3a,11a,20 triheptanoyloxy-17(20)-pregnene; and 3a,11ot,20 trioctanoyloxy- 17(20)-pregnene.

PREPARATION ..-1 7 -oxIDo-3 a,11ot,20- TRIACETOXYPREGNANE One andone-half grams of 3u,11a,20 triacetoxyl7(20)-pregnene (Preparation 13)was dissolved in 7.5 milliliters of chloroform, and the solution wascooled in an ice bath to about five degrees centigrade. Three andthree-tenths milliliters of commercial grade forty percent peraceticacid solution in which 100 milligrams of sodium acetate had beendissolved was added, and the re sulting mixture was then shaken on amechanical shaking machine for about two hours at room temperature tocomplete the reaction. The mixture containing the crude product wasdiluted with fifty milliliters of methylene chloride and then washedwith several -milli1iter portions of ice-cold five percent aqueoussodium hydroxide solution followed by 25-milliliter portions of wateruntil the wash solution was neutral to pH test paper. The neutralsolution was dried with anhydrous sodium sulfate and then filtered toremove the drying agent. The white crystalline residue obtained onevaporating the solvent from the clear, dry solution melted at 210-213degrees centigrade. Recrystallization from a mixture of ethyl acetateand Skelly Solve B gave fluffy needles of 17 (20)-oxido-3a,11a-20-triacetoxypregnane, melting at 214-217 degreescentigrade.

Analysis:

Calculated for C27H40Or. C, 68.04; H, 8.46 Found C, 68.33; H, 8.62 C,67.90; H, 8.38

PREPARATION 16.--17(20)-0XIDO-3/3,11a,20- 'I'RIACETOXYPREGNANE Usingthis procedure described in Preparation 15,3p,1la,20-triacetoxy-17(20)-pregnene from Preparation 14 is converted to17 (20)-oxido-3,8,1la,20-triacetoxypregnane by oxidation with peraceticacid in the presence of sodium acetate.

In the same manner as given above in Preparation 15 and Preparation 16,other 17(20)-OXidO-3a(0l' fi):110t,20- triacyloxy pregnanes are preparedfrom the corresponding 3a(or ,8),11a,20-triacyloxy-17(20)-pregnenes,including 17 20 -oxido-3 a,11u,20-tripropionoxypregnane; 17 20 oxido 33,11oc,2O tripropionoxypregnane; 11a acetoxy- 313,20-dipropionoxy-17(20)-oxidopregnane; 11a formyloxy-3 3,20-diacetoxy-l 7 20) -oxidopregnane;17 20) -oxido-3 a, l 1a,20-trioctanoyloxypregnane; 35,20-dioctanoyloxy-l7(20)-oxido-1lot-propionoxypregnane; 17 (20)-oxido-3a,11a-20-tributyryloxypregnane; 17 20) .-oxido-3q',-1la,20-trivaleryloxypregnane; 17 (20) -OXldO-3cc, 1lot,20-trihexanoyloxypregnane; 17(20)"OXidO'3OL,1106,20-tflh6P-tanoyloxypregnane; l7(20)-oxido-3 oc,1 la,20-trioctanyloxypregnane; andthe like.

PREPARATION 17.-1 1ot-AcEToxY-3u,17a-DrHYRoxYPREo- NAN-ZO-ONE AND306,1lot,170c-TRIHYDROKYPREGNAN-20- ONE Nine hundred milligrams of17(20)-OXidO-3a,11a,20- triactaoxypregnane (Preparation 15) wasdissolved in fifty milliliters of alcohol, and to the resulting solutionwas added with swirling 11.3 milliliters of a 0.5 normal aqueous sodiumhydroxide solution. After standing at room temperature for thirtyminutes, the solution Was extracted with chloroform, and the chloroformextract was then washed with twenty percent aqueous sodium chloridesolution and dried with anhydrous sodium sulfate. The drying agent wasremoved by filtration, and the solvent was removed by evaporation underreduced pressure giving the product as a colorless, viscous oil. The oilwas dissolved in 100 milliliters of benzene, and the solution was passedthrough a chromatographic column packed with ninety grams of Florisilmagnesium silicate to absorb the product. The product was eluted fromthe column by washing with the following solvent mixtures in succession:Ten IOU-milliliter portions of 5 percent acetone and percent SkellySolve B, ten -milliliter portions of 10 percent acetone and 90 percentSkelly Solve B, and ten IOU-milliliter portions of 20 percent acetoneand 80 percent Skelly Solve B. On evaporation of the solvents from thevarious fractions, the product had been separated into two parts, bothcolorless viscous oils. The product from the first fractions was1lu-acetoxy-3u,17a-dihydroxypregnan-20-one, as confirmed by analyticaldata, and the product from the later fractions was3a,11a,17octrihydroxypregnan-ZO-one, identical with the3a,11a,l7a-trihydroxypregnan-ZO-one obtained in Preparation 2. The ratiowas about one part of the acetoxy compound for every nine parts of thetrihydroxy compound.

Analysis of l1ot-acetoxy-3u,l7a-dihydroxypregnan-20- one:

Calculated for C23H3605 C, 70.37; H, 9.25

Found C, 70.30; H, 9.30

PREPARATION 18.11a-AcEToxY-3,B,17a DIHYDROXYPREG- NAN-20-oNB AND33,11a,17a-TR1nYuRoxYPREoNAN-20- ONE hydroxypregnan-ZO-one and3p,l1u,17ot-trihydroxypregnan-ZO-one, as confirmed by analytical data.The ratio was about one part of the acetoxy compound for every ten partsof the trihydroxy compound.

Analysis of 1lot-acetoxy-3,B,17a-dihydroxypregnan-20- one:

Calculated for C23H3605 C, 70.37; H, 9.25 Found C, 70.43; H, 9.19Analysis of 3,8,1la,17a-trihydroxypregnan-20-one:

Calculated for Cz1Ha4O4 C, 71.96; H, 9.78 Found C, 71.80; H, 9.82

In the same manner as given above in Preparation 17 and Preparation 18,other 11a-acyloxy-3u(or {3),l7-dihydroxypregnan-ZO-ones are prepared,including 3a,l7a-dlhydroxy 11a. formyloxypregnane-20-one;3a,l7oc-dihydroxy-l 1ot-prOpiOnoxypregnan-ZO-one; 3 ,8,17-dihydroxyl1u-propionoxypregnan-ZO-one; 11a-butyryloxy-3u,17-dihydroxypregnan-20-one; 3 a,17-dihydroxy-11a-valery1oXy pregnan-ZO-one; 3a, l7-dihydroxy-l 1a-hexanoy1oxypregnan-ZO-one; 3a,l7-dihydroxy-lla-heptanoyloxypregnan- ZO-One;3a,17-dihydroxy-1 1a-octanoyloxypregnan-ZO-one; and the like, dependingon the starting material employed.

PREPARATION 19.-21-BROMo-3 a,]. 1oz, 17oc-TRIHYDROXY- PREoNAN-20-ONE30,11a,17a-trihydroxypregnan-ZO-one (Preparation 2 or 17), dissolved inchloroform, is treated with a solution of bromine in chloroform at aboutforty degrees centigrade. After completion of the bromination, thechloroform is distilled to give a theoretical yield of 21-bromo- 311,1111,17 a-trihydroxypregnan-ZO-one; melting point 122.5 to 127 degreescentigrade.

PREPARATION 20.2 1-BRoMO-3 a, 1 1 [3, 1 7ot-TRIHYDROXY- PREGNAN-ZO-ONE3a,l15,17a-trihydroxypregnan-20-one (Preparation 2), brominated as inPreparation 19 yields 21-brOn1o-3 01,1 1,6,-17a-trihydroxypregnan-20-one in nearly quantitative yield.

PREPARATION 21.21BROM0-3[3,110,l7oc-TRIHYDROXY- PREGNAN-ZO-ONEBromination of 3fi,11or,17a-trihydroxypregnan-20-one (Preparation 8 or18) using the procedure of Preparation 19 gives21-bro1no-36,11a,17a-trihydmxypregnan-ZO-one in high yield.

PREPARATION 22.-21-BR0M0-35,1 15, 17oL-TRIHYDROXY- PREGNAN-ZO-ONETreatment of 3 p, 1 1,8,17a-trihydroxypregnan-ZO-one (Preparation 8)with bromine in chloroform, according to the procedure of Preparation 19yields 21-bromo- 313,1lfl,l7m-trihydroxypregnan-ZO-one.

PREPARATION 23.21-BR0M0-1 1ot-ACETOXY-3c,17oc DIHY- DROXYPREGNAN-ZO-ONEPREPARATION 24.21-ERoM0-1 l0cACETOXY-3B,17ot- DIHYDROXYPREGNAN-ZO-ONEBromination of 1lot-acetoxy-3/3,l7u-dihydroxypregnan- 20-one(Preparation 18) using the method of Preparation 19, gives21-b10m0-11OL-3C6'COXY-3fi,l70t-dlhyd1OXypregnan-20-one in nearlytheoretical amounts.

In the same manner other 21-bromo-1lot-acyloxy-3/3,17wdihydroxypregnan-20-ones are prepared from corresponding 11ot-acyloXy-3B,17ot-dihydroxypregnan-20-ones, including ZI-hromo-lloz-formyloxy 3,8,17m dihydroxypregnane-ZO-one; 21 bromo 11cc propionoxy313,17- dihydroxypregnan-ZO-one; 21-bromo-1 1ot-butyryloxy3fi, 17ot-dihydroxypregnan-20-one; 21-bromo-l1a-valeryloxy-3,3,17a-dihydroxypregnan-20-one; 21 bromo 11ahexanoyloxy-3fl,l7a-dihydroxypregnan 20 one; 21-bromo- 11aheptanoyloxy-3fl,17ot-dihydroxypregnan-20-one; 21- bromo- 11a-octanoyloxy-3fl,17a-dihydroxypregnan-ZO-one; and the like.

PREPARATION 25 .2 1 -CHLORO-3 oc,1 1a,17a-TR1HYDR0XY- PREGNAN-ZG-ONE Asolution of 3a,11a,17a-trihydroxypregnan-ZO-one (Preparation 2 or 17) incarbon tetrachloride is treated with chlorine, dissolved in carbontetrachloride, at about room temperature. Distillation of the carbontetrachloride solvent gives 21-chloro-3a,11a,17x-trihydroxypregnan-ZO-one in excellent yield.

In the same manner other 21-chloro-3,17a-dihydroxy-11-oxygenated-pregnan-20-ones are obtained from corresponding 3,1701dihydroxy 11 oxygenated-pregnan-ZO- ones, including2l-chloro-3tx,l1B,17ot-trihydroxypregnan- 20-one;2l-chlorof3fl,l1a,17u-trihydroxypregnan-20-one; 21-chloro 3fi,1l B,l7atrihydroxypregnan 20 one; 21- chloro-11ot-acetoxy-3a,17adihydroxypregnan 20 one; 21ChlOI'O-llot-PI'OPlOIlOXY-BOL,17ot-dlhYdlOXYPf6gl'1fil'l-20- one;21-chloro-11abutyryloxy-3a,l7or-dihydroxypregnan- 20-one; 21-chloro 11avaleryloxy 304,170L dihydroxypregnan-ZO-one; 21 chloro 11a hexanoyloxy300,170:- dihydroxypregnan-ZO-one; 21 chloro-11ix-heptanoyloxy-311,17a-dihydrOXypregnan-ZO-one; 21-chloro 11aoctanoyloXy-3a,17a-dihydroxypregnan-20-one;21-chl0ro-11aformyloxy-3B,17a-dihydroXypregnane-20-one; 21-chloro- 11a-acetoxy-3 B, 17 u-dihydroXypregnan-20-one; 21-chlorolla propionoxy35,17a dihydroxypregnan-ZO-one; 21-chloro-l1ot-butyryloxy-3B,l7a-dihydroxypregnan-20 one;21-chloro-11a-valeryloxy 313,17oz dihydroxypregnan-20- one; 21chloro-11ot-heXanoyloxy-3fl,17a-dihydroxypregnan-ZO-one; 21 chloro 11ccheptanoyloxy-3fl,17a-dihydroxypregnan-ZO-one; 21-chloro-11ot-octanoyloxy-3fi,17adihydroxypregnan-ZO-one; and the like.

PREPARATION 26.21-AcEToxY-3 00,1 111,17 oc-TRIHYDROXY- PREONAN-ZO-ONE 21bromo 3oc,llot,l7ct trihydroxypregnan 20 one (Preparation 19), dissolvedin acetone is heated for about sixteen hours under reflux with excessanhydrous potassium acetate in the presence of a trace of potassiumiodide and a trace of acetic acid. The resulting solution is cooled andthen diluted with water to precipitate the 21-acet0xy-3a,1 1a,17oc-trihydroxypregnan-20-one; melting point 185 to 189 degreescentigrade. The yield is nearly quantitative.

In the same manner other 21-aCy1OXy-30t,110C,170L-trihydroxypregnan-ZO-ones are prepared from 21-brorno-3a,1la,17a-trihydroxypregnan-ZO-one, and the appropriate potassiumacylate, including 21-formyloxy-3a,11a, 17 a-trihydroxypregnan 20 one;21-propionoxy-3u,11a, 17a trihydroxypregnan 20 one; ZI-butyryloxy-MJ 1a,17u-trihydroxypregnan-20-one; 21-valeryloxy-3a,1 101,170:-trihydroxypregnan-ZO-one; 21hexanoyloxy-3a,l1a,17atrihydroxypregnan-20-one; 21-heptanoyloxy-3a, 1104,170:- trihydroxypregnan 2O one; 21-octanoyloxy-3ct,1 101,171tribydroxypregnan-ZO-one; and the like.

PREPARATION 27 .-2 1-AcEToxY-3 oz, 1 1B,17u-TRIHYDROXY PREGNAN-ZO-ONEReplacement of the bromine atom in 21-bromO-3a,l111,17oc-trihydroxypregnan-20-one (Preparation 20) by an acetoxy groupis accomplished in the same manner as in Preparation 26. The yield of21-acetoxy-3et,11,8,17a-trihydroxypregnan-ZO-one is the theoreticalamount.

In the same manner other2l-acyloxy-3u,11p,17a-trihydroxy-pregnan-ZO-ones are prepared from21-brorno- 3u,l1B,17a-trihydroxypregnan-20-one and the appropriatepotassium acylate, including 21-formyloxy-3u,1l 8, 17a-trihydroxypregnan20 one; 21 p1-opi0noxy-3oc,1lfl, l7a-trihydroxypregnan 20 one; 21butyryloxy-3ot,l 1p, 17u-trihydroxypregnan-20-one; 21-va1erylOxy-3 a, 1118,170:- trihydroxypregnan 20-one; 21 hexanoyloxy3a,11,8,17atrihydroxypregnan 20 one; 21 heptanoyloxy 3a,11fl,

" 17ot-trihydroxypregnan-20-one; 21 octanoyloxy 30,1l5,

17a-trihydrOXy regnan-ZO-one; and the like.

PREPARATION 28.21-ACETOXY3fl,1 la, 1 7 a-TRIHYDROXY- PREGNAN-ZQ-ONE 21bromo 3[3,11oc,17u trihydroxypregnan 20 one (Preparation 21) isconverted to 21-acetoxy-35,11a,17atribydroxypregnan-ZO-one by the methodof Preparation 26.

In the same manner other 21-acyloxy313,lla,l7ot-trihydroxypregnan-ZO-ones are prepared from 21-bromo-PREPARATION 29.-21-AcEToxY-3B, 1 1B,17a-TR1HYDROXY- PREGNAN-ZO-ONEAccording to the procedure of Preparation 26, 21- bromo-Sp, 11,8,17u-trihydroxypregnan--one (Preparation 22) is converted to21-acetoxy-3fi,11;8,17a-trihydroxypregnan-ZO-one in high yield.

In the same manner other21-acyloxy-3;3,11,3,17a-trihydroxypregnan-ZO-ones are prepared from21-bromo- 35,11,8,17a-trihydroXypregnan-ZO-one and the appropriatepotassium acylate, including 21-formyloxy- 3,8,115,17ot-trihydroxypregnan-20-one; 21-propionoxy- 313,1 15,17atrihydroxypregnan 20 one; 21-butyryloxy- 35,115,170 trihydroxypregnan 20one; ll-valeryloxy- Bfl, 1 1,6,17a-trihydrQXypregnan-ZO-one;21-hexanoy1oxy- 319,11,8,17a-trihydroxypregnan-20-one; 21-heptanoyloxy-313,1 1,8,17a-trihydroxypregnan-20-one; 21-octanoyloxy-3,8,11B,17a-trihydroxypregnan-ZO-one; and the like. PREPARATION30.-11a,21-DIAcEToxY-3m,17a-DIHYDR0XY- PREGNAN-ZO-ONE Using the methodof Preparation 26, 11a,21-diacetoxy- 3, 17a-dihydroxypregnan-20-one isproduced from 21- bromo 110a -acetoxy 3a,17a dihydroxypregnan 20- one(Preparation 23).

In the same manner other 11a,21-diacyloxy-3a,17udihydroxypregnan-ZO-onesare prepared from the appropriate 21-bromo-1 1a-acyloxy-3 oz,17a-dihydroxypregnan-ZO-one and the appropriate potassium acylate,ineluding 21-acetoxy 11oc formyloxy -3u,170tdihydroxypregnan-ZO-one;21-propionoxy -1 laacetoxy 611,170; -dihydroxypregnan 20- one;21-butyryloxy 11oz acetoxy- 3m,17ot dihydroxypregnan -20- one;21-valeryloxy llaacetoxy-3a,17a-dihydroxypregnan-ZO-one; 21-hexanoy1-oxy -11aacetoxy -3ot,l7ocdihydroxypregnan -20- one; 21-heptanoyloxy-11aacetoxy -3cc,17ozdihydroxypregnan -20- one; 21-octanoyloxy-11ozdroxypregnan 20 one; 11:1,21 dipropionoxy 311,17ocdihydroxypregnan-20- one; 110;,21- dibutyryloxy -3 a,17udihydroxypregnan-ZO-one;11u,21-dihexanoyloxy-3a,17udihydroxypregnan-ZO-one;11m,21-dicotanoyloxy-3a,17adihydroxypregnan -20- one; 21-acetoxy-11apropionoxy- 3a,17a-dihydroxypregnan-ZO-one; and the like.

PREPARATION 3 1 .-1 1u,21-DIAcEToxY-3B, 1 7a-DIHYDROXY- PREGNAN-ZO-ONE21-bromo 110a acetoxy 3 3,170: dihydroxypregnan- 20-one (Preparation 24)is treated with potassium acetate according to the procedure ofPreparation 26 to give 11a,21 diacetoxy 35,1711 dihydroxypregnan 4 20one in high yield.

In the same manner other11a,21-diacyloxy-3;3,17adihydroxypregnan-ZO-ones are prepared from theappropriate 21 bromo 11cc acyloxy 313,17 dihydroxypregnan-ZO-one and theappropriate potassium acylate, including 2l-formyloxy -11aacetoxy-3fl,17adihydroxypregnan -20- one; 21-propionoxy-l1aacetoxy-3/3,17a-dihydroxypregnan 20 one; 21-butyryloxy 11cc acetoxy-3- 3,17a-dihydroxypregnan 20 one; 21 valeryloxy llaacetoxy-3fl,17ocdihydroxypregnan -20 -one; 21-hexanoyloxy-lla-acetoxy 63,171dihydroxypregnan -20- one; 21- heptanoyloxy-11u-acetoxy-3p,17adihydroxypregnan-ZO- one;21-octanoyloxy-l1a-acetoXy-SB,17a-dihydroxypregnan-20-one; 11a,21-dipropionoxy-3;3,17u-dihydroxypregnan-one; 11u,21-dibutyryloxy-3B,17a-dihydroxypregnan- 20-one; 11a,21-dihexanoyloxy-3p, 17 m-dihydroxypregnan- 20-one; 11a,21-dioctanoyloxy-3/8,17m-dihydroxypregnan- 14 20-one; ZI-acetoxy-l1m-propionoxy-3fl,17or-dihydr0xy pregnan-ZO-one; and the like.

The 21-acyloxysteroids obtained in Preparation 26 through Preparation 31from the 21-bromosteroids may also be obtained in the same manner bysubstituting the corresponding 2l-chlorosteroid (Preparation 25) for the21-bromosteroid specified.

Example 1 .4-ch loro-l 7a-hydrwcypregnane-3J1,20- trione A solution of25 grams of 3u,17a-dihydroxypregnane- 11,20-dione [Sarett, J. Am. Chem.Soc., 70, 1454 (1948)] in 380 milliliters of tertiary-butyl alcohol isadmixed with five milliliters of concentrated hydrochloric acid andtwelve milliliters of water, and thereafter cooled to about fifteendegrees Centigrade. Eighteen milliliters (2.2 molar equivalents) oftertiary-butyl hypochlorite is then added thereto, whereupon thetemperature rises to about 26 degrees Centigrade. The reaction mixtureis stirred for 4.5 hours although the iodometric titration of an aliquotsample taken from the reaction mixture after two hours shows thereaction to be essentially complete. The volatile components of thereaction mixture then are removed by distillation under reduced pressureleaving a 24.6 gram residue (a yield of 91 percent of the theoretical,corrected for the samples taken from the reaction mixture for iodometrictitrations) of 4-chloro- 17u-hydroxypregnane-3,11,20-trione which meltswithout purification at 220 to 225 degrees centigrade and has an [aJ ofplus 91 degrees (acetone).

In the same manner 36,l7ot-dihydroxypregnaned1,20- dione (Preparation 6)is converted to 4-chloro-17ahydroxypregnane-3,1 1,20-trione.4-chl01'0-17oc-hYdl'OXY- pregnane-3,11,20-trione is a stable, readilypurifiable compound having a well defined crystalline structure. Unlike4-bromo -17uhydroxypregnane -3,11,20- trione, said compound does notdecompose on standing and is storable for long periods withoutdecomposition. Treatment of said compound with semicarbazidehydrochloride and thereafter with pyruvic acid is productive of theknown 17u-hydroxy -4- pregnene -3,11,20'- trione [Kritchevsky et al., J.Am. Chem. Soc. 74, 483 (1952)]. Treatment of4-ch1oro-17a-hydroxypregnane-3,11,20-trione with bromine in acetic acidis productive of 4-chloro- 17a-hydroxy-21-bromopregnane-3,11,20-trione,which, as shown in Example 6, can be converted to cortisone acetate intwo steps.

Example 2.4-ch Zora-1 7 a-h ydr0xypregnane-3,1 1 ,20- trione Analysis:

Calculated for C21H2904Cl Cl, 9.31 Found Cl, 9.24

Example 3.4 chl0r0-17u-hydr0ucy-21-acetoxypregnane- 3,11,20-tri0ne To asolution of 0.50 gram of 3a,17 x-dihydroxy-2lacetoxypregnane-l1,20-dioneESarett, J. Am. Chem. Soc., 70, 1454 (1948)] in eighteen milliliters oftertiary-butyl alcohol is added 0.75 milliliter of water, 0.1 milliliterof concentrated hydrochloric acid, and 0.52 milliliter (0.5 gram, 3.69millimoles) of tertiarybutyl hypochlorite. The resulting solution isdiluted to 25 milliliters. with tertiarybutyl alcohol and the wholestirred in the dark for about 22 hours. The crystalline precipitate of4-chloro-17a (10 millimoles) oftertiaryhydroxy-Zl-acetoxypregnane-3,11,20-trione is then filtered,washed with a small portion of tertiary butyl alcohol and air-dried. Theyield of precipitated product melting with decomposition at 232 to 236.5degrees centigrade and having an [al of plus 99 degrees (acetone) is0.325 gram, a yield of 60.2 percent of the theoretical. The infraredspectrum is consistent with the assigned structure. A further quantityof product remains in the filtrate and is recovered therefrom.

4-ChlOIO-l70t hydroxy 21 acetoxypregnane 3,11,20- trione isdehydrohalogenated by treatment with semicarbazide hydrochloridefollowed by treatment with pyruvic acid to obtain cortisone acetate.

Example 4.4-chl0r0-17a hydroxy-ZI -acetxypregnane- 3,11 ,ZO-trione Inexactly the same manner as described in Example 3, using the samereactants but omitting the hydrochloric acid, 4chloro-17ot-hydroxy-2l-acetoxypregnane-3,11,20- trione precipitates fromthe reaction mixture in a yield of 48.1 percent of the theoretical. Afurther quantity of product is isolated by concentration of theresulting filtrate.

Example .-4 chloro-17ot-hydr0xy-21-acet0xypregnane- 3,11,20-tri0ne Inexactly the same manner as described in Example 3 and using the samereactants but substituting fifty milligrams of paratoluenesulfonic acidfor the hydrochloric acid, 4chloro-l7ec-hydroxy-2l-acetoxypregnane-3,11,20- trione precipitates fromthe reaction mixture in a yield of 51 percent of the theoretical amount.As in Examples 2 and 3, more product is isolated from the remainingfiltrate.

In the same manner as Shown in Example 3 through Example 5, other4-chloro-l7a-hydroxy-2l-acyloxypregnane-3,ll,20-triones are preparedfrom corresponding 3,l7a-dihydroxy-2l-acyloxypregnane-l 1,20-dione,including 4-chloro-l7ot-hydroxy-2 l-formyloxypregnane-3,1 1,20- trione;4 chloro 17a hydroxy-2l-propionoxypregnane- 3,11,20-trione; 4chloro-17a-hydroxy-2l-butyryloxypregmane-3 ,1 1,20-trione;4-chloro-17a-hydroxy-2l-valeryloxypregnane-3,ll,20-trione; 4 chlorol7a-hydroxy-2l-hexanoy1oxypregnane-3,l1,20-trione; 4 chloro-l7whydroxy-2l-heptanoyloxypregnane-3,l1,20 trione; 4chloro-171xhydroxy-2l-octanoyloxypregnane-3,1l,20-trione; and the like.

Example 6.-4 chloro-17a-hydr0xy-21-br0m0pregnane- 3,11,20-trione Asolution of two grams of 3a,l7udihydroxy-2l-bromopregnane-l 1,20-dione[Kritchevslty et al., J. Am. Chem. Soc., 74, 483 (1952)] in fiftymilliliters of tertiarybutyl alcohol containing 1.5 milliliters of waterand 0.38 milliliter of concentrated hydrochloric acid is contacted with1.12 milliliters of tertiary butyl hypochlorite for 3.5 hours, at theend of which time the hypochlorite is completely consumed. The solutionis then diluted with twice its volume of water whereupon the theoretical2.17 grams of 4 chloro-17a-hydroxy-2l-bromopregnane-3,l1,20-trioneprecipitates.

Analysis:

Calculated for C21H28ClB1'O4 Total halogen, 25.10 Found Total halogen,24.42

4-chloro-17ot-hydroxy-2l-bromopregnane-3 ,1 1,20-trione also is obtainedin exactly the same manner as above using the same reactants butsubstituting tertiary-amyl hypochlorite for the tertiary-butylhypochlorite.

4-ChlOIO-l7oc-hYdl0XY-2 l -bromopregnane-3 ,11,2'0-trione is a stablecompound and does not decompose on standing. The presence of a halogenatom at carbon atom four and at carbon atom 21 renders the compound avaluable precursor to known physiologically active cortical hormones.Dehydrohalogenation with semicarbazide hydrochloride followed by pyruvicacid gives l7a-hydroxy-2lbromo-4-pregnene-3,11,20-trione. Subsequenttreatment with potassium acetate in acetone gives cortisone acetate.

Example 7 .4,21 -dichl0r0-1 7ot-hydr0xypregnane- 3,11,20-tri0ne composeon standing. Dehydrohalogenation followed by' treatment with potassiumacetate gives cortisone acetate as in Example 6.

Example 8.-4 chloro-11oc-hydroxypregnane-3,20-dione Using the procedureof Example 1, 3rx,lloc-dihydroxypregnan-20-one (Preparation 11) isconverted to 4-chlorollwhydroxypregnan 3,20-di0ne. Dehydrohalogenation.

of the product with pyridine yields the known 11ahydroxyprogesterone.

Example 9.-4-chl0r0-17a-hydroxypregnane- 3,11,20-tri0ne' In the samemanner asdescribed'in Example 1, a solution of 350 milligrams of3ot,115,17a-trihydroxypregnan- 20-one (Preparation 2) in fifteenmilliliters of tertiarybutyl alcohol was reacted with 0.22 gram oftertiarybutyl hypochlorite in the presence of water and hydrochloricacid. After ten minutes, all the active chlorine of the reaction mixturehad been consumed. The solvent was then distilled at reduced pressureand the theoretical 380 milligram residue recrystallized from isopropylalcohol to give 4-chloro-l7a-hydroxypregnane-3,l1,20-trionc,' identicalwith the product of Example 1, and which did not depress the meltingpoint of an authentic sample, the yield being almost the theoreticalamount.

In the same manner as shown above, 3,6,1lfi,17a-trihydroxypregnan-ZO-one(Preparation 8) is converted to 4-chloro-l7a-hydroxypregnane-3,l1,20-trione.

Example 10.4-chl0ro-11 a,17a-dihydr0xypregnane 3,20-di0ne To a solutionof 3a,11a,17a-trihydroXypregnane-ZO- one (Preparation 2 or 17) inaqueous tertiary-butyl alcohol containing hydrochloric acid is addedtertiarybutyl hypochlorite, and, after mixing, the resulting solution isallowed to stand at room temperature with occasional shaking, theprocedure of Example 3 being fol lowed. After the theoretical amount oftertiary-butyl hypochlorite is reacted, as determined by iodometrictitration, the product begins to precipitate. The crystalline 4-chloro-l1a,17a-dihydroxypregnane-3,20-dione is recovered by filtration.The remainder of the product is obtained as a solid residue when theremaining filtrate is evaporated, the total yield being nearly thetheoretical amount; melting point 183 to 185 degrees centigrade.Analysis: I

Calculated for CZlI'IBlOCl Cl, 9.26 Found Cl, 9.30

In the same manner 35,11a,17a-trihydroxypregnan-20- one (Preparation 8or 18) is converted to 4-chlorol1a,17a-dihydroxypregnane-3,20-dione.Mild oxidation of 4-chloro-l1a,17a-dihydroxypregnane-3,20-dione withchromic acid in acetic acid solution gives4-chl0ro-17ahydroxypregnane-3,11,20-tri0ne (Example 1).

1 7 Example 1] .4-chlor0-1 1 a-acetoxy-l 7m-hydroxypregnane-3,20-dioneAnalysis:

Calculated for C23H33O5C1 Cl, 8.34 Found Cl, 8.58

in the same manner other4ChlOIO-1Izx-EICYIGXY-17ochydroxypregnane-3,ZO-diones are prepared from11aacyloxy-3e (or t2),171x-dihydroxypregnan-ZO-ones, including4-ch1oro-1 lot-formyloxy-17a-hydroxypregnane-3,20- dione; 4chloro-1la-propionoxy-17a-hydroxyprcgnane- 3,20 dione;4-chloro-1lot-butyryloxy-l7m-hydroxypregnane-3,20-dione; 4chloro-1la-valeryloxy-17u-hydroxypregnane 3,20 dione; 4chloro-1lot-hexanoyloxy-lhhydroxypregnane-3,ZO-dione; 4-chloro-llot-heptanoyloxy- 17ct-hydroxypregnane-3,20-dione;4-chloro-11a-octanoyloxy-l7a-hydroxypregnane-3,20-dione; and the like.

The 4-chloro-1 1a-acyloxy-17u-hydroxypregnane-3,20- diones may beconverted to cortisone acetate by brominating at the 21-position usingbromine in acetic acid to produce the2l-bromo-4-chloro-1lueacyloxy-lh-hydroxypregnane-3,20-diones,dehydrohalogenating with pyridine to remove hydrogen chloride and obtain2l-brorno-11aacyloxy-l 7a-hydroxy-4-pregnene-3,20-diones, hydrolyzingthe 2l-bromine and the llu-acyloxy group to produce11a,17e,21-trihydroxy-4-pregnene-3,ZO-dione using sodium hydroxide inaqueous alcohol, acetylating the 21- hydroxyl group with one equivalentof acetic anhydride in pyridine to produce21-acetoxy-11e,17a-dihydroxy-4- pregnene-3,20-dione, and mildlyoxidizing the Ila-hydroxy group with chromic acid in acetic acid toproduce an eleven-keto group.

Example ]2.-4-chl0r0-21-br0m0-1104,1 7a-clihydr0xypregnane-3,20-dineFollowing the method of Example 6, 21-bromo-3u;11u,17a-trihydroxypregnan one (Preparation 19) gives 4 chloro21-bromo-11a,17u-dihydroxypregnane- 3,20-dione in excellent yield. Inthe same manner 4- chloro 21 bromo 110.,170; dihydroxypregnane-3,20-dione is obtained from 2l-bromo-3fi,11a,17a-trihydroxypregnan-ZO-one(Preparation 21).

Mild oxidation of the 11ot-hydroxy group of 4-chloro-ZI-bromo-l1a,17u-dihydroxypregnane-3,20-dione gives 4- chloro 21-bromo-17a-hydroxypregnane3,l1,20-trione which can be converted tocortisone acetate as shown in Example 6.

Example 13 .4-ch lore-21 -br0m0-I 7u-hydr0xypregane- 3,11,20-tr1'0neAccording to the procedure of Example 9, 21-bromo-311,11,8,17a-trihydroxypregnan-ZO-one (Preparation 20) is converted to4-chloro-2l-bromo-l7a-hydroxypregnane- 3,11,20-trione in essentially aquantitative yield; melting point 168 to 174 degrees centigrade. In thesame manner 21-bromo-3fi,11 B,17a-trihydroxypregnan-ZO-one (Preparation22) yields 4-chloro-21-brorno-17a-hydroxypregname-3,11,20-trioneidentical with the product of Example 6, and which may be converted tocortisone acetate as shown in Example 6.

Example J4.-4-chl0r0-21-brom0-11a-acet0xy-17ahydroxypregnane-3,20-di0ne21 bromo 1la-acetoxy-iie,17a-dihydroxypregnan-20- one is treated withtertiary-butyl hypochlorite according to the method of Example 3 toobtain 4-chloro-21-bromo- 1 11a-acetoxy-17a-hydroxypregnane-3,ZG-dione.Use of the starting compound2l-bromo-1Ia-acetOXy-SBJM-dihydroxypregnan-ZO-one also gives4-chloro-21bromo-11o.- acetoxy-17u-hydroxypre nane-3,ZO-dione in highyield in the same manner other 4Cl1l0IO-2lb10Il10-.1la acyloxyhydroxypregnane-3,ZO-diones are prepared from the correspondingZI-bromo-l la-acyloxy-3e(or [3),- 17a dihydroxypregnan 2(l-ones,including 4-chloro-2lbromo 11a formyloxy-17a-hydroxypregnane3,ZO-dione;4 chloro 21 bromo-1lu-propionoxy-l7a-hydroxypregmane-3,20-dione;4-chloro-21-bromo-1lebutyryloxy-l7ahydroxypregnane-3,20-dione; 4chloro-Zl-bromo-l 10- valeryloxy-l7a-hydroxypregnane-3,20-dione;4-chloro-21- bromo 11cc hexanoyloxy 17ot=hydroxypregnane-3,20- dione; 4chloro 21 bromo-1lot-heptanoyloxy-l7u-hy droxypregnane-3,ZO-dione;4-chloro-21-bromo-1lot-octanoyloxy-l7a-hydroxypregnane-3,20-dione; andthe like.

4 chloro-2l-bromo-l lm-acyloxy-l7a-hydroxypregnane- 3,20-diones may beconverted to cortisone acetate as shown in Example 11.

Example 15.-4,21-d1'chl0ro-1 1 (1,1 7a-dihydr0xypregnane-3,20-di0ne2lchloro-3a,11a,17a-trihydroxypregnan-ZO-one (Preparation 25) isconverted, according to the method of Example 1, to4,2l-dichloro-11a,17a-dihydroxypregnane- 3,20-dione, the weight ofsteroid product being about the same as the weight of starting steroid.

in the same manner other4,21dichloro-1-oxygenatedl7a-hydroxypregnane-3,ZO-diones are preparedfrom corresponding 21-chloro 11 oxygenated3,17a-dihydroxypregnan-20-ones, including 4,21-dichloro-l la-forniyloxy-17cc hydroxypregnane-3,QO-dione;4,2l-dichl.oro-11o-propionoxy-l7a-hydroxypregnane-3,ZO-dione; 4,21dichloro- 11a-butyryloxy-17ct-hydroxypregnane 3,20 dione; 4,21-dlchloro- 1 lwvaleryloxy- 1 7o-hydroxypregnaue6 ,ZD-dione;4,21-dichloro-1lu-hexanoyloxy 17a. hydroxypregnane- 3 Ell dione;4,21dichloro-1 1 a-heptanoyloxy-17(x-hydroxypregnane-3,20-dione;4,21-dichloro-1 lwoctanoyloxy-lhhydroxypregnane-3,20-dione; and thelike. The 21-chloro derivative may be converted to cortisone acetate inthe same manner as the ZI-brorno derivatives of Example 12 throughExample 14.

Example 16.4-chl0r0 21 acetoxy-I]m,17ot-dihyr0xypregnane-3,20-di0neUsing the method of Example 1,2l-acetoxy-3ct,11o,17atrihydroxypregnan-20-one (Preparation 26) givesalmost the theoretical weight of4-chloro-21-acetoxy-1la,l7adihydroxypregnane-3,20-dione. In the samemanner 21- acetoxy 3,8,11a,17u-trihydroxypregnan-M)-one (Preparation 28)is converted to4-chloro-21acetoxy-110,1'7a-dihydroxypregnane-3,ZO-dione.

Other 4-chloro-21-acyloxy-1 1u,17wdihydroxypregnane* 3,20-diones areprepared from the appropriate 2l-acyloxy- 301(01' e),lla,17a-trihydroxypregnan-ZO-ones in the same manner, including4-chloro-21-formyloxy-11u,17a-dihydroxypregnane-3,ZO-dione; 4chloro-2l-propionoxy-l1oz,- 17cc dihydroxypregnane-3,20-dione;4-chloro-2l-butyryloxy-l 1a,17e-dihydroxypregnane-3,ZG-dione;4-chloro-21- valeryloxy l1rx,l7oz dihydroxypregnane-B,ZO-dione; 4-chloro-2l-hexanoyloxy-11a,l7u-dihydroxypregnane 3,20- dione;4-chloro-2l-heptanoyloxy-l10,17a dihydroxypre nane'3,20-dione; 4Cl'llOlO-Zl-OCtflnOYlOXY-l1oc,17oc-dlhY- droxypregnane-3,20-dione; andthe like.

4-chloro-2l-acyloxy-lla,17a-dihydroxypregnane 3,20- diones are oxidizedwith chromic acid in acetic acid under mild conditions to obtain4-chloro-21acyloxy-17a-hydroxypregnane-3,1LZQ-triones which areconvertible to cortisone acylates as shown in Example 3 for cortisoneacetate preparation.

Example 17.-4-chl0r0-21-acetoxy-I7u-hydr0xypregnane- 3,11,20-lri0ne21-acetoxy-3 x,1 1B,17a-trihydroxypregnan-20-one (Preparation 27) istreated with about 4.2 molar equivalents of tertiary-butyl hypochloriteaccording to the method of Example 9 to give nearly the theoreticalquantity of 4- chloro-21-acetoxy-17ot-hydroxypregnane 3,11,20 trione;melting point 233-237 degrees Centigrade. The same prodnot is obtainedin the same manner starting with 21- acetoxy-3B,11,8,17a-trihydrQXypregnan-ZO-one.

In the same manner other4-chloro-21-acyloxy-17a-hydroxypregnane-3,11,20-triones are preparedfrom corresponding 21-acyloxy-3a(or ,8),l1,8,17u-trihydroxypregnan-20-ones, including4-chloro-2l-formyloxy-l'ia-hydroxypregnane-3,11,20-triones;4-chloro-21-propionoxy-17a-hydroxypregnane-3,1 1,20-triones; 4-chloro 21butyryloxy- 17a-hydroxypregnane-3, 1 I-ZO-triones;4-chloro-2l-valeryloxy-17m-hydroxypregnane-3,1 1,20-triones; 4 chloro21- hexanoyloxy 17a hydroxypregnane-3,11,20-triones; 4- chloro 21heptanoyloxy-17a-hydroxypregnane-3,11,20- triones; 4chloro-21-octanoyloxy-17a-hydroxypregnane- 3,11,20-triones; and thelike.

4-chloro-21-acyloxy 170a hydroxypregnane 3,11,20 triones are convertibleto cortisone acylates as shown in Example 3 for cortisone acetatepreparation.

Example 18.4-chl0r0-11o,21 diacetoxy 17a-hydr0xypregnane-3,20-dineTreating 1 1u,21-diacetoxy-3a,17a-dihydroxypregnan-20- one (Preparation30) with tertiary butyl hypochlorite according to the procedure ofExample 1 gives high yields of4-chloro-11a,21-diacetoxy-l7oahydroxypregnane 3,20- dione. In the samemanner 11u,21-diacetoxy-3B,17a-dihydroxypregnan-ZO-one (Preparation 31)is converted to 4-chloro-1lu,21-diacetoxy 17a hydroxypregnane-3,20-dione in comparable yield.

Other 4-chloro-1la,21-diacyloxy-17a-hydroxypregnane- 3,20-diones areprepared from 11a,21-diacyloxy-3a(or B),17a-dihydroxy-pregnan--ones inthe same manner, including 4-chloro-11a acetoxy 21 formyloxy17a-hydroxypregnane-3,20-dione; 4chloro-l1a-acetoxy-21-propionoxy-17a-hydroxypregnane-3,20-dione; 4ChlOIO-llotacetoxy-Z1-butyryloxy-17u-hydroxypregnane-3,20 dione;4-chlor0-1 1a-acetoxy-2l-valeryloxy-17a-hydroxypregnane 3 ,20-dione;4-chloro-1 1a-acetoxy-2 1 -hexanoyloxy- 1 7a-hydroxypregnane-3,20-dione;4 chloro-I 1oc-acetoxy-21-heptanoyloxy-17a-hydroxypregnane-3,20-dione;4-chloro-1 10cacetoxy-Zl-octanoyloxy-17a-hydroxypregnane-3,20-dione; 4chloro-l1a,2l-diformyloxy-17m-hydroxypregnane-3,20- dione;4-chloro-11m,21-dipropionoxy 170a hydroxypregnane-3,20-dione;4-chloro-11u,21-dibutyryloxy 170a hydroxypregnane-3,ZO-dione; 4-chloro11et,21 dihexanoyloxy- 1 7or-hydroxypregnane-3 ,ZO-dione; 4-chloro-1la,21 -dioctanoyloxy-17a-hydroxypregnane-3,20-dione; 4 chloro- 110apropionoxy-2l-acetoxy-17ot-hydroxypregnane 3,20- dione; and the like.

Treatment of 4-chloro-11a,21-diacyloxy-17ot-hydroxypregnane-3,20-dioneswith semicarbazide hydrochloride followed by pyruvic acid gives11a,21-diacyloxy-17orhydroxy-4-prcgnene-3,20-diones. Saponification ofthese diacyloxypregnenes with sodium hydroxide in aqueous alcohol gives11m,17o,21-trihydroxy-4-pregnene-3,20-dione which may be converted tocortisone acetate as shown in Example 11.

Example 19.4-chl0r0pregnane-3,20-di0ne One gram of3a-hydroxypregnan-20-one dissolved in fifty milliliters oftertiary-butyl alcohol containing 1.5 milliliters of water and 0.4milliliter of concentrated hydrochloric acid is admixed with 0.85 gramof tertiarybutyl hypochlorite, and the resulting mixture is allowed tostand at room temperature with occasional shaking. After about two hoursthe product begins to precipitate and is recovered by filtration; weight0.4 gram; melting point 178-183 degrees centigrade. An additional 0.5gram of 4-chloropregnane-3,ZO-dione is recovered from the filtrate byevaporating the solution to dryness.

In the same manner as described in Example 1 through Example 19, other3-hydroxysteroids are converted to 4-cl1loro-3-ketosteroids usingtertiary-butyl, tertiary-amyl, or other organic hypochlorite such as,for example, propyl hypochlorite, hexyl hypochlorite, octylhypochlorite, or the like. Steroids thus-produced, which may bedehydrohalogenated as shown in the above examples to give A-3-ketosteroids, include the following: coprostanol or epicoprostanolgives 4-chlorocoprostanone which on dehydrohalogenation gives the knownA -cholestenone; 3a(or ,8)-hydroxy-2l-acetoxypregnane-l1,20-dione or31x- (or -,8),1lfi-dihydroxy-Zl-acetoxypregnan-ZO-one gives4-chloro-21-acetoxypregnane-3,11,20-trione which on dehydrohalogenationyields the known 21-acetoxy-4-prcgnene-3,11,20-trione; 3u(orB)-hydroxy-l7-isoetiocholanic acid gives4-chloro-3-keto-17-isoetiocholanic acid which on dehydrohalogenationyields the known 3-keto-17-iso-A etiocholenic acid; 3a(orB)-hydroxypregnane-11,20-dione gives 4-chloropregnane-3,11,20-trionewhich on dehydro halogenation yields the known4-pregnene-3,11,20-trione; 304(01 [3),11B-dihydroxypregnan-20-one alsogives 4-chloropregnane-3,11,20-trione; and other like examples.

It is to be understood that the invention is not to be limited to theexact details of operation or exact compounds shown and described asobvious modifications and equivalents will be apparent to one skilled inthe art and the invention is therefore to be limited only by the scopeof the appended claims.

We claim:

1. A process which comprises: contacting a saturated 3-hydroxysteroidwith an organic hypochlorite in the presence of water.

2. A process which comprises: contacting a saturated 3-hydroxysteroidwith an alkyl hypochlorite in the presence of water.

3. A process for the conversion of a 3-secondary-hydroxysteroid to a4-chloro-3-ketosteroid by simultaneous oxidation and chlorination whichcomprises: contacting a saturated 3-secondary-hydroxysteroid which isunsubstituted at the 4-position and which has the normalstereoconfiguration at the S-carbon atom with an alkyl hypochloritecontaining more than one carbon atom, in the presence of an organicsolvent, and in the presence of water in amount up to about twentypercent of the reaction mixture by weight, at a temperature betweenabout minus ten and about plus fifty degrees Centigrade, to produce a4-chloro-3-ketosteroid.

4. A process for the conversion of a 3-seeondary-hydroxysteroid to a4-chloro-3-ketosteroid by simultaneous oxidation and chlorination whichcomprises: contacting a saturated 3,11a-disecondary-hydroxysteroidcontaining no primary or other secondary-hydroxy groups and which isunsubstituted at the 4-position and has the normal configuration at theS-carbon atom with an alkyl hypochlorite containing more than one carbonatom, in the presence of an organic solvent, and in the presence ofwater in amount up to about twenty percent of the reaction mixture byweight, at a temperature between about minus ten and about plus fiftydegrees centigrade, to produce a 4-chloro-3-keto,1la-hydroxysteroid.

5. A process for the conversion of a 3-secondary-hydroxysteroid to a4-chloro-3-ketosteroid by simultaneous oxidation and chlorination whichcomprises: contacting a saturated 3,11fl-disecondary-hydroxysteroidcontaining no primary or other secondary-hydroxy groups and which isunsubstituted at the 4-position and has the normal configuration at theS-carbon atom with an alkyl hypochlorite containing more than one carbonatom, in the presence of an organic solvent, and in the presence ofwater in amount up to about twenty percent of the reaction mix.- ture byWeight, at a temperature between about minus ten and about plus fiftydegrees centigrade, to produce a 4-chloro-3 ,1 l-diketosteroid.

6. A process for the conversion of a 3-secondaryhydroxysteroid to a4-chloro-3-ketosteroid by simultaneous oxidation and chlorination whichcomprises: contacting a saturated 11-keto-3-secondairy-hydroxysteroidcontaining no primary or other secondary-hydroxy groups and which isunsubstituted at the 4-position and has the normal configuration at the5-carbon atom with an alkyl hypochlorite containing more than one carbonatom, in the presence of an organic solvent, and in the presence ofwater in amount up to about twenty per cent of the reaction mixture byweight, at a temperature between about minus ten and about plus fiftydegrees centigrade, to produce a 4-chloro-3,1l-diketosteroid.

7. A process for the conversion of a 3-secondary-hydroxysteroid to a4-chloro-3-ketosteroid by simultaneous oxidation and chlorination whichcomprises: contacting a saturated 11-keto-3-secondary-hydroxysteroidcontaining no primary or other secondary-hydroxy groups and which isunsubstituted at the 4-position and has the normal configuration at theS-carbon atom, with at least about two molar equivalents oftertiary-butyl hypochlorite, in the presence of an organic solvent andan acid, and in the presence of water in amount up to about twentypercent of the reaction mixture by weight, at a temperature betweenabout twenty and about thirty degrees centigrade, to produce a4-chloro-3,ll-diketosteroid.

8. A process for the conversion of a 3-secondary-hydroxysteroid to a4-chloro-3-ketosteroid by simultaneous oxidation and chlorination whichcomprises: contacting a saturated 3,11tx-disecondary-hydroxysteroidcontaining no primary or other secondary-hydroxy groups and which isunsubstituted at the 4-position and has the normal configuration at theS-carbon atom, with at least about two molar equivalents oftertiary-butyl hypochlorite, in the presence of an organic solvent andan acid, and in the presence of water in amount up to about twentypercent of the reaction mixture by weight, at a temperature betweenabout twenty and about thirty degrees centigrade, to produce a4-chloro-3-keto-1lot-hydroxysteroid.

9. A process for the conversion of a 3-secondaryhydroxysteroid to a4-chloro-3-ketosteroid by simultaneous oxidation and chlorination whichcomprises: contacting a saturated 3,11,9-disecondary-hydroxysteroidcontaining no primary or other secondary-hydroxy groups and which isunsubstituted at the 4-position and has the normal configuration at theS-carbon atom, with at least about four molar equivalents oftertiary-butyl hypochlorite, in the presence of an organic solvent andan acid, and in the presence of water in amount up to about twentypercent of the reaction mixture by weight, at a temperature betweenabout twenty and about thirty degrees centigrade, to produce a4-ch1oro-3,ll-diketosteroid. 10. A process for the conversion of aS-secondaryhydroxysteroid to a 4-ch1oro-3-ketosteroid by simultaneousoxidation and chlorination which comprises: contacting3,l7a-dihydroxypregnane-11,20-dione with between about 2.2 and about 2.5molar equivalents of tertiary-butyl hypochlorite, in the presence oftertiary-butyl alcohol and between about 0.5 and about 1.5 molarequivalents of hydrogen chloride, and in the presence of water in amountup to about twenty percent of the reaction mixture by weight, at atemperature between about twenty and about thirty degrees centigrade, toproduce 4-chloro- 17a-hydroxypregnane-3,1 1,20-trione.

11. A process for the conversion of a S-secondaryhydroxysteroid to a4-chloro-3-ketosteroid by simultaneous oxidation and chlorination whichcomprises: contacting 3,17a-dihydroxy-2l-bromopregnane-11,20-dione withbetween about 2.2 and about 2.5 molar equivalents of tertiary-butylhypochlorite, in the presence of tertiarybutyl alcohol and between about0.5 and about 1.5 molar equivalents of hydrogen chloride, and in thepresence of water in amount up to about twenty percent of the reactionmixture by weight, at a temperature between about twenty and aboutthirty degrees centigrade, to produce 4-chloro-17a-hydroxy -21-bromopregnane-3,11,20-trione.

12. A process for the conversion of a 3-secondaryhydroxysteroid to a4-chloro-3-ketosteroid by simultaneous oxidation and chlorination whichcomprises: contacting a 3,17a-dihydroxy-2l-acyloxypregnane-l1,2()-dionewith between about 2.2 and about 2.5 molar equivalents of tertiary-buty1hypochlorite, in the presence of tertiary-butyl alcohol and betweenabout 0.5 and about 1.5 molar equivalents of hydrogen chloride, and inthe presence of water in amount up to about twenty percent of thereaction mixture by weight, at a temperature between about twenty andabout thirty degrees centigrade, to produce a4-chloro-17a-hydroxy-21-;acyloxypregnane- 3,11,20-trione.

13. A process for the conversion of a 3-secondaryhydroxysteroid to a4-chloro-3-ketosteroid by simultaneous oxidation and chlorination whichcomprises: con tacting a 3,1la,17u-trihydroxy-2l-acyloxypregnan-ZO-onewith between about 2.2 and about 2.5 molar equivalents of tertiary-butylhypochlorite, in the presence of tertiarybutyl alcohol and between about0.5 and about 1.5 molar equivalents of hydrogen chloride, and in thepresence of water in amount up to about twenty percent of the reactionmixture by weight, at a temperature between about twenty and aboutthirty degrees centigrade, to produce a g -chloro-11u,l7a-dihydroxy 21acyloxyprepnane-3,20-

lone.

14. A process for the conversion of a 3secondary hydroxysteroid to a4-chloro-3-ketosteroid by simultaneous oxidation and chlorination whichcomprises: contacting a 3,11p,17a-trihydroxy-2l-acyloxypregnan-ZO-onewith between about 4.2 and about 4.5 molar equivalents of tertiary-butylhypochlorite, in the presence of tertiarybutyl alcohol and between about0.5 and about 1.5 molar equivalents of hydrogen chloride, and in thepresence of water in amount up to about twenty percent of the reactionmixture by weight, at a temperature between about twenty and aboutthirty degrees centigrade, to produce a4-chloro-17a-hydroxy-2l-acyloxypregnane- 3, 1 1,20-trione.

15. A process for the conversion of a 3-secondaryhydroxysteroid to a4-chloro-3-ketosteroid by simultaneous oxidation and chlorination whichcomprises: contacting a steroid of the following formula:

wherein R is selected from the group consisting of whydroxy andfi-hydroxy; R1 is selected from the group consisting of hydrogena-hydroxy, a-acyloxy, ,B-hydroxy, and ketonic oxygen; R2 is selectedfrom the group consisting of hydrogen and hydroxy; and R3 is selectedfrom the group consisting of acetyl, bromoacetyl, chloroacetyl, andacyloxyacetyl; with at least about two molar equivalents of atertiary-alkyl hypochlorite, in the presence or an organic solvent, andin the presence of water in amount up to about twenty percent of thereaction mixture by weight, at a temperature between about minus ten andabout plus fifty degrees centigrade, to produce a 4-chloro-3-ketosteroid.

References Cited in the file of this patent UNITED STATES PATENTS2,403,683 Reichstein July 9, 1945 2,541,104 Sarett Feb. 13, 1951

1. A PROCESS WHICH COMPRISES; CONTACTING A SATURATED 3-HYDROXYSTEROID WITH AN ORGANIC HYPOCHLORITE IN THE PRESENCE OF WATER. 